Current projections predict pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths surpassing breast, prostate and colorectal cancers by 2030. Lack of treatment strategies that can reduce the near equal incidence and mortality rate is a barrier for this disease. A key feature of PDAC is desmoplasia, which is characterized by increased fibrosis and inflammation. Desmoplasia plays a critical role not only in pancreas pathogenesis but also in tumor maintenance and limiting therapeutic efficacy by decreasing drug access to the tumor. Pancreatic stellate cells (PSCs) present in the tumor microenvironment (TME) are major contributors to desmoplasia. Accordingly, targeting tumor-stromal interactions by reprogramming PSC activation has emerged as a new therapeutic strategy and led to drugs such as Nab-Paclitaxel in combination with Gemcitabine. However their utility have been limited. Therefore, we propose that in addition to ?reprogramming PSC activation? disruption of PSC interaction with pancreatic cancer cells (PCCs) is critical for effective PDAC inhibition. We have identified a new compound (Palmatine; PMT) that shows preliminary evidence of fitting this paradigm. We have hypothesized that ?PMT-mediated inhibition of sonic hedgehog (Shh) from PCCs that mediates activation of GLI/COL1A1 axis in PSCs and releases COL1A1 into the TME will disrupt activation of PSC as well as its interaction with PCCs to inhibit fibrosis associated with desmoplasia?. This hypothesis will be tested using relevant cell culture and preclinical animal models in three specific aims. Aim 1 studies will test the hypothesis that activation of Shh from PCCs leads to activation of GLI/COL1A1 axis in PSCs and subsequent release of COL1A1 into the extracellular space to facilitate interaction with PCCs and PMT will inhibit this paracrine interaction. Pharmacological, genetic inhibition and rescue approaches will be combined with biochemical and functional assays to address these studies in co-culture and conditioned media culture conditions. Aim 2 studies will test the hypothesis that PMT disrupts paracrine interaction between PCC-PSC in vivo to suppress PDAC development using the pre-clinical LSL K-ras G12D+; LSL-Trp53R172H/+; Pdx-1Cre transgenic model (KPC mice). Histopathological evaluation of pancreas including tumor grade and metastasis, tissue levels of molecular markers, tissue and serum levels of PMT and serum metabolite alterations will be assessed. Aim 3 studies test the hypothesis that PMT will inhibit GLI, COL1A1, in short-term ex vivo cultures of patient-derived pancreatic tissues. Impact of the study: This paradigm changing study will establish the notion that targeting the activation of PSC and inhibiting its interaction with PCC is required to provide therapeutic efficacy for PDAC. Pancreatic cancer patient tissues will provide evidence of the usefulness of PMT against human PDAC; and set the stage for clinical translation. Further this study will also identify molecules that can be developed as markers to predict therapeutic resistance/sensitivity, which will also have significant translational potential.